WO2006113150A1 - Agonistes du recepteur de la niacine, compositions les contenant et methodes de traitement - Google Patents

Agonistes du recepteur de la niacine, compositions les contenant et methodes de traitement Download PDF

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Publication number
WO2006113150A1
WO2006113150A1 PCT/US2006/012876 US2006012876W WO2006113150A1 WO 2006113150 A1 WO2006113150 A1 WO 2006113150A1 US 2006012876 W US2006012876 W US 2006012876W WO 2006113150 A1 WO2006113150 A1 WO 2006113150A1
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compound
mmol
added
solution
compounds
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PCT/US2006/012876
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English (en)
Inventor
Jason E. Imbriglio
Steven L. Colletti
James R. Tata
Rui Liang
Subharekha Raghavan
Darby R. Schmidt
Abigail R. Smenton
Sook Yee Chan
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Merck & Co., Inc.
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Priority to AU2006236939A priority Critical patent/AU2006236939A1/en
Priority to EP06740649A priority patent/EP1874301A4/fr
Priority to JP2008506525A priority patent/JP2008536846A/ja
Priority to CA002603757A priority patent/CA2603757A1/fr
Priority to US11/918,270 priority patent/US20090054423A1/en
Publication of WO2006113150A1 publication Critical patent/WO2006113150A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to compounds, compositions and methods of treatment or prevention in a mammal relating to dyslipidemias.
  • Dyslipidemia is a condition wherein serum lipids are abnormal. Elevated cholesterol and low levels of high density lipoprotein (HDL) are associated with a greater-than-normal risk of atherosclerosis and cardiovascular disease.
  • Factors known to affect serum cholesterol include genetic predisposition, diet, body weight, degree of physical activity, age and gender.
  • cholesterol in normal amounts is a vital building block for essential organic molecules such as steroids, cell membranes, and bile acids
  • cholesterol in excess is known to contribute to cardiovascular disease.
  • cholesterol is a primary component of plaque which collects in coronary arteries, resulting in the cardiovascular disease termed atherosclerosis.
  • Niacin or nicotinic acid is a drug that reduces coronary events in clinical trials. It is commonly known for its effect in elevating serum levels of high density lipoproteins (HDL). Importantly, niacin also has a beneficial effect on other lipid profiles.
  • LDL low density lipoproteins
  • VLDL very low density lipoproteins
  • TG triglycerides
  • nicotinic acid is limited by a number of adverse side-effects including cutaneous vasodilation, sometimes called flushing.
  • the present invention relates to compounds that have been discovered to have effects in modifying serum lipid levels.
  • the invention thus provides compositions for effecting reduction in total cholesterol and triglyceride concentrations and raising HDL, in accordance with the methods described. Consequently one object of the present invention is to provide a nicotinic acid receptor agonist that can be used to treat dyslipidemias, atherosclerosis, diabetes, metabolic syndrome and related conditions while minimizing the adverse effects that are associated with niacin treatment. Yet another object is to provide a pharmaceutical composition for oral use.
  • n 1 or 2;
  • R 1 is selected from the group consisting of cyclohexyl, phenyl and heteroaryl containing 5-6 atoms, said heteroaryl 5-membered rings containing 1-4 heteroatoms, 0-1 of which are O or S and 0-4 of which are N, and said Heteroaryl 6-membered rings containing 1-3 N atoms, said cyclohexyl, phenyl and heteroaryl being optionally substituted with 1-4 members selected from the group consisting of: halogen, OH, SH, CN, nitro, Ci -4 haloalkyl, amino, C 1-4 alkylamino, C 2-S dialkylamino, Ci -4 alkyl, Ci -4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, Ci. 4 haloalkoxy, Ci ⁇ alkylthio, Ci -4 alkylsulfmyl, and Ci. 4 alkylsulfonyl,
  • Alkyl as well as other groups having the prefix "alk”, such as alkoxy, alkanoyl and the like, means carbon chains which may be linear, branched, or cyclic, or combinations thereof, containing the indicated number of carbon atoms. If no number is specified, 1-6 carbon atoms are intended for linear and 3-7 carbon atoms for branched alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like.
  • Cycloalkyl is a subset of alkyl; if no number of atoms is specified, 3-7 carbon atoms are intended, forming 1-3 carbocyclic rings that are fused. "Cycloalkyl” also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and the like.
  • alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
  • Alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3 -methyl- 1-pentynyl, 2-heptynyl and the like.
  • Heteroaryl (HAR) unless otherwise specified, means a mono- aromatic ring or ring system containing at least one heteroatom selected from O, S and N, with 5 to 6 atoms. Examples include, but are not limited to, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl and the like. Heteroaryl also includes such groups in charged form, e.g., pyridinium.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • flushing refers to the elimination of measurable cutaneous flushing, e.g., a side effect that is often seen when nicotinic acid is administered in therapeutic amounts.
  • the flushing effect of nicotinic acid usually becomes less frequent and less severe as the patient develops tolerance to the drug at therapeutic doses, but the flushing effect still occurs to some extent and can be transient.
  • flushing in the absence of substantial flushing refers to the reduced severity of flushing when it occurs, or fewer flushing events than would otherwise occur.
  • the incidence of flushing is reduced by at least about a third, more preferably the incidence is reduced by half, and most preferably, the flushing incidence is reduced by about two thirds or more.
  • the severity of flushing is preferably reduced by at least about a third, more preferably by at least half, and most preferably by at least about two thirds. Clearly a one hundred percent reduction in flushing incidence and severity is most preferable, but is not required.
  • One aspect of the invention relates to a compound of Formula I:
  • n 1 or 2;
  • R 1 is selected from the group consisting of cyclohexyl, phenyl and heteroaryl containing 5-6 atoms, said heteroaryl 5-membered rings containing 1-4 heteroatoms, 0-1 of which are O or S and 0-4 of which are N, and said Heteroaryl 6-membered rings containing 1-3 N atoms, said cyclohexyl, phenyl and heteroaryl being optionally substituted with 1-4 members selected from the group consisting of: halogen, OH, SH, CN, nitro, C 1-4 haloalkyl, amino, Ci -4 alkylamino, C 2- s dialkylamino, C 1-4 alkyl, C 1-4 alkoxy, C 2- 4alkenyl, C 2-4 alkynyl, C 3 . 6 cycloalkyl, Q-
  • R ⁇ is H or C I-4 alkyl.
  • One subset of compounds that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein n is 1. Within this subset, all other variables are as originally defined.
  • Another subset of compounds that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein n is 2. Within this subset, all other variables are as originally defined.
  • Another subset of compounds that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate there of wherein R 1 represents phenyl or heteroaryl, said group being optionally substituted with 1-4 groups, 1-4 of which are halo groups and 1-2 of which are selected from the group consisting of: OH, SH, CN, nitro, C 1-4 haloalkyl, amino, C 1-4 alkylamino, C 2- s dialkylamino, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 1-4 haloalkoxy, C 1- 4 alkylthio, C 1-4 alkylsulfinyl, and C 1-4 alkyls
  • R 1 represents phenyl optionally substituted with 1-4 groups, 1-4 of which are halo groups and 1-2 of which are selected from the group consisting of: OH, SH, CN, nitro, C 1-4 haloalkyl, amino, Ci -4 alkylamino, C 2-8 dialkylamino, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 1-4 haloalkoxy, C 1-4 alkylthio, C 1-4 alkylsulfinyl, and C 1 . 4 alkylsulfonyl.
  • R 1 represents phenyl optionally substituted with 1-4 groups, 1-4 of which are halo groups and 1-2 of which are selected from the group consisting of: OH, SH, CN, nitro, C 1-4 haloalkyl, amino, Ci -4 alkylamino, C 2-8 dialkylamino, C 1-4
  • R 1 represents heteroaryl optionally substituted with 1-4 groups, 1-4 of which are halo groups and 1-2 of which are selected from the group consisting of: OH, SH, CN, nitro, C 1-4 haloalkyl, amino, C 1-4 alkylamino, C 2-8 dialkylamino, Q- 4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 1-4 haloalkoxy, C 1-4 alkylthio, C 1- 4 alkylsulfmyl, and C 1-4 alkylsulfonyl.
  • R 1 represents heteroaryl optionally substituted with 1-4 groups, 1-4 of which are halo groups and 1-2 of which are selected from the group consisting of: OH, SH, CN, nitro, C 1-4 haloalkyl, amino, C 1-4 alkylamino, C 2-8 dialkylamino, Q- 4 alkyl, C
  • Another subset of compounds that is of particular interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein R 1 represents phenyl optionally substituted with 1-4 halo groups. Within this subset, all other variables are as originally defined.
  • Another subset of compounds that is of interest relates to compounds of formula I or a pharmaceutically acceptable salt or solvate thereof wherein R 2 represents CO 2 R a and R a represents H. Within this subset, all other variables are as originally defined.
  • Another subset of compounds that is of interest relates to compounds of formula I or a pharmaceutically acceptable salt or solvate thereof wherein R 2 represents tetrazolyl. Within this subset, all other variables are as originally defined.
  • the dosages of compounds of formula I or a pharmaceutically acceptable salt or solvate thereof vary within wide limits.
  • the specific dosage_regimen and levels for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the patient's condition. Consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective orprophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition.
  • the compounds will be administered in amounts ranging from as low as about 0.01 mg/day to as high as about 2000 mg/day, in single or divided doses.
  • a representative dosage is about 0.1 mg/day to about 1 g/day. Lower dosages can be used initially, and dosages increased to further minimize any untoward effects. It is expected that the compounds described herein will be administered on a daily basis for a length of time appropriate to treat or prevent the medical condition relevant to the patient, including a course of therapy lasting months, years or the life of the patient.
  • additional active agents may be administered with the compounds described herein.
  • the additional active agent or agents can be lipid modifying compounds or agents having other pharmaceutical activities, or agents that have both lipid-modifying effects and other pharmaceutical activities.
  • additional active agents which may be employed include but are not limited to HMG-CoA reductase inhibitors, which include statins in their lactonized or dihydroxy open acid forms and pharmaceutically acceptable salts and esters thereof, including but not limited to lovastatin (see US Patent No. 4,342,767), simvastatin (see US Patent No. 4,444,784), dihydroxy open-acid simvastatin, particularly the ammonium or calcium salts thereof, pravastatin, particularly the sodium salt thereof (see US Patent No.
  • HMG-CoA synthase inhibitors include squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors including selective inhibitors of ACAT-I or ACAT-2 as well as dual inhibitors of ACAT-I and -2; microsomal triglyceride transfer protein (MTP) inhibitors; endothelial lipase inhibitors; bile acid sequestrants; LDL receptor inducers; platelet aggregation inhibitors, for example glycoprotein Ilb/lUa fibrinogen receptor antagonists and aspirin; human peroxisome proliferator activated receptor gamma (PPAR-gamma) agonists including the compounds commonly referred to as glitazones for example pioglitazone and rosiglitazone and, including those compounds included within the structural
  • Cholesterol absorption inhibitors can also be used in the present invention. Such compounds block the movement of cholesterol from the intestinal lumen into enterocytes of the small intestinal wall, thus reducing serum cholesterol levels.
  • Examples of cholesterol absorption inhibitors are described in U.S. Patent Nos. 5,846,966, 5,631,365, 5,767,115, 6,133,001, 5,886,171, 5,856,473, 5,756,470, 5,739,321, 5,919,672, and in PCT application Nos. WO 00/63703, WO 00/60107, WO 00/38725, WO 00/34240, WO 00/20623, WO 97/45406, WO 97/16424, WO 97/16455, and WO 95/08532.
  • ezetimibe also known as l-(4- fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone, described in U.S. Patent Nos. 5,767,115 and 5,846,966.
  • Therapeutically effective amounts of cholesterol absorption inhibitors include dosages of from about 0.01 mg/kg to about 30 mg/kg of body weight per day, preferably about 0.1 mg/kg to about 15 mg/kg.
  • the compounds used in the present invention can be administered with conventional diabetic medications.
  • a diabetic patient receiving treatment as described herein may also be taking insulin or an oral antidiabetic medication.
  • an oral antidiabetic medication useful herein is metformin.
  • metformin an oral antidiabetic medication useful herein.
  • the compounds of formula I can be co-dosed with a vasodilation suppressing agent. Consequently, one aspect of the methods described herein relates to the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in combination with a compound that reduces flushing.
  • DP prostaglandin D2 receptor
  • CRTH2 another prostaglandin D2 receptor
  • the present invention utilizes antagonism of the DP receptor to prevent, minimize or reduce flushing that otherwise may occur.
  • Doses of the DP receptor antagonist and selectivity are such that the DP antagonist selectively modulates the DP receptor without substantially modulating the CRTH2 receptor.
  • the DP receptor antagonist ideally has an affinity at the DP receptor (i.e., K;) that is at least about 10 times higher (a numerically lower Kj value) than the affinity at the CRTH2 receptor. Any compound that selectively interacts with DP according to these guidelines is deemed "DP selective".
  • Dosages for DP antagonists as described herein, that are useful for reducing or preventing the flushing effect in mammalian patients, particularly humans, include dosages ranging from as low as about 0.01 mg/day to as high as about 100 mg/day, administered in single or divided daily doses. Preferably the dosages are from about 0.1 mg/day to as high as about 1.0 g/day, in single or divided daily doses.
  • the compound of formula I or a pharmaceutically acceptable salt or solvate thereof and the DP antagonist can be administered together or sequentially in single or multiple daily doses, e.g., bid, tid or qid, without departing from the invention.
  • sustained release such as a sustained release product showing a release profile that extends beyond 24 hours, dosages may be administered every other day.
  • single daily doses are preferred.
  • morning or evening dosages can be utilized.
  • Salts and Solvates Salts and solvates of the compounds of formula I are also included in the present invention, and numerous pharmaceutically acceptable salts and solvates of nicotinic acid are useful in this regard.
  • Alkali metal salts in particular, sodium and potassium, form salts that are useful as described herein.
  • alkaline earth metals in particular, calcium and magnesium, form salts that are useful as described herein.
  • Various salts of amines, such as ammonium and substituted ammonium compounds also form salts that are useful as described herein.
  • solvated forms of the compounds of formula I including hydrates, such as the hemihydrate, mono-, di-, tri- and sesquihydrate are of particular interest.
  • the compounds used in the present invention can be administered via any conventional route of administration.
  • the preferred route of administration is oral.
  • compositions described herein are generally comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable carrier.
  • suitable oral compositions include tablets, capsules, troches, lozenges, suspensions, dispersible powders or granules, emulsions, syrups and elixirs.
  • carrier ingredients include diluents, binders, disintegrants, lubricants, sweeteners, flavors, colorants, preservatives, and the like.
  • diluents include, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate and sodium phosphate.
  • granulating and disintegrants include corn starch and alginic acid.
  • binding agents include starch, gelatin and acacia.
  • lubricants include magnesium stearate, calcium stearate, stearic acid and talc.
  • the tablets may be uncoated or coated by known techniques. Such coatings may delay disintegration and thus, absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a compound of formula I or a pharmaceutically acceptable salt or solvate thereof is combined with another therapeutic agent and the carrier to form a fixed combination product.
  • This fixed combination product may be a tablet or capsule for oral use.
  • a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (about 1 to about 1000 mg) and the second therapeutic agent (about 1 to about 500 mg) are combined with the pharmaceutically acceptable carrier, providing a tablet or capsule for oral use.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • the dosage form may also be coated by the techniques described in the U.S. Patent Nos.
  • Typical ingredients that are useful to slow the release of nicotinic acid in sustained release tablets include various cellulosic compounds, such as methylcellulose, ethylcellulose, propylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, starch and the like.
  • a tablet as described above, comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and further containing an HMG Co-A reductase inhibitor, such as simvastatin or atorvastatin.
  • This particular embodiment optionally contains the DP antagonist as well.
  • Typical release time frames for sustained release tablets in accordance with the present invention range from about 1 to as long as about 48 hours, preferably about 4 to about 24 hours, and more preferably about 8 to about 16 hours.
  • Hard gelatin capsules constitute another solid dosage form for oral use. Such capsules similarly include the active ingredients mixed with carrier materials as described above.
  • Soft gelatin capsules include the active ingredients mixed with water-miscible solvents such as propylene glycol,
  • PEG and ethanol or an oil such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions are also contemplated as containing the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia; dispersing or wetting agents,e.g., lecithin; preservatives, e.g., ethyl, or n-propyl para-hydroxybenzoate, colorants, flavors, sweeteners and the like.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredients in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Syrups and elixirs may also be formulated. More particularly, a pharmaceutical composition that is of interest is a sustained release tablet that is comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and a DP receptor antagonist that is selected from the group consisting of compounds A through
  • compositions that is of more interest are comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and a DP antagonist compound selected from the group consisting of compounds A, B, D, E, X, AA, AF, AG, AH, AI and AJ, in combination with a pharmaceutically acceptable carrier.
  • a DP antagonist compound selected from the group consisting of compounds A, B, D, E, X, AA, AF, AG, AH, AI and AJ, in combination with a pharmaceutically acceptable carrier.
  • composition in addition to encompassing the pharmaceutical compositions described above, also encompasses any product which results, directly or indirectly, from the combination, complexation or aggregation of any two or more of the ingredients, active or excipient, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical composition of the present invention encompasses any composition made by admixing or otherwise combining the compounds, any additional active ingredient(s), and the pharmaceutically acceptable excipients.
  • Another aspect of the invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and a DP antagonist in the manufacture of a medicament.
  • This medicament has the uses described herein.
  • another aspect of the invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, a DP antagonist and an HMG Co-A reductase inhibitor, such as simvastatin, in the manufacture of a medicament.
  • This medicament has the uses described herein.
  • Compounds of the present invention demonstrate anti-hyperlipidemic activity, indicative of utility for reducing LDL-C, triglycerides, apolipoprotein a and total cholesterol, and increasing HDL- C. Consequently, the compounds of the present invention are useful in treating dyslipidemias.
  • the present invention thus relates to the treatment, prevention or reversal of atherosclerosis and the other diseases and conditions described herein, by administering a compound of formula I or a pharmaceutically acceptable salt or solvate in an amount that is effective for treating, preventing or reversing said condition.
  • a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective to treat or prevent said condition, while preventing, reducing or minimizing flushing effects in terms of frequency and/or severity.
  • One aspect of the invention that is of interest is a method of treating atherosclerosis in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating atherosclerosis in the absence of substantial flushing.
  • Another aspect of the invention that is of interest relates to a method of raising serum HDL levels in a human patient in need of such treatment, comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for raising serum HDL levels.
  • Another aspect of the invention that is of interest relates to a method of treating dyslipidemia in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating dyslipidemia.
  • Another aspect of the invention that is of interest relates to a method of reducing serum VLDL or LDL levels in a human patient in need of such treatment, comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for reducing serum VLDL or LDL levels in the patient in the absence of substantial flushing.
  • Another aspect of the invention that is of interest relates to a method of reducing serum triglyceride levels in a human patient in need of such treatment, comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for reducing serum triglyceride levels.
  • Another aspect of the invention that is of interest relates to a method of reducing serum
  • Lp(a) levels in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for reducing serum Lp(a) levels.
  • Lp(a) refers to lipoprotein (a).
  • Another aspect of the invention that is of interest relates to a method of treating diabetes, and in particular, type 2 diabetes, in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating diabetes.
  • Another aspect of the invention that is of interest relates to a method of treating metabolic syndrome in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating metabolic syndrome.
  • Another aspect of the invention that is of particular interest relates to a method of treating atherosclerosis, dyslipidemias, diabetes, metabolic syndrome or a related condition in a human patient in need of such treatment, comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and a DP receptor antagonist, said combination being administered in an amount that is effective to treat atherosclerosis, dyslipidemia, diabetes or a related condition in the absence of substantial flushing.
  • Another aspect of the invention that is of particular interest relates to the methods described above wherein the DP receptor antagonist is selected from the group consisting of compounds A through AJ and the pharmaceutically acceptable salts and solvates thereof.
  • nicotinic acid receptor has been identified and characterized in
  • DP receptor antagonists can be obtained in accordance with WO01/79169 published on October 25, 2001, EP 1305286 published on May 2, 2003, WO02/094830 published on November 28, 2002 and WO03/062200 published on July 31, 2003.
  • Compound AB can be synthesized in accordance with the description set forth in WO01/66520A1 published on September 13, 2001;
  • Compound AC can be synthesized in accordance with the description set forth in WO03/022814A1 published on March 20, 2003, and
  • Compounds AD and AE can be synthesized in accordance with the description set forth in WO03/078409 published on September 25, 2003.
  • Other representative DP antagonist compounds used in the present invention can be synthesized in accordance with the examples provided below.
  • hydrazine can be used in place of benzylhydrazine-HCl, and the resultant pyrazole can be protected as its N-toluenesulfonamide 3.
  • the ethyl enol ether can be selectively hydrolyzed under acidic conditions, and the resultant ketone converted to its enol triflate by methods known to those skilled in the art, providing common intermediate 4.
  • cyclohexane-l,4-dione mono-ketal can be acylated with a dialkyloxalate, the beta-diketone cyclized with benzylhydrazine-HCl, and the ketal hydrolyzed to ketoester 5.
  • This ketone can then be converted to its enol triflate by methods known to those skilled in the art, providing common intermediate 6.
  • hydrazine can be used in place of benzylhydrazine-HCl, and the ketal hydrolyzed to ketoester 7.
  • the resultant pyrazole 7 can be protected as its N-toluenesulfonamide, and the ketone converted to its enol triflate by methods known to those skilled in the art, providing common intermediate 8.
  • Common intermediate 2 can be converted to compounds such as 9 via Suzuki coupling, which installs the C5 moiety, followed by tetrazole ring synthesis, and a concomitant reduction of the olefin with debenzylation under hydrogenation conditions (Scheme 3).
  • Common intermediate 4 can also be converted to compounds such as 10 via Suzuki coupling, to install the C5 moiety, followed by sequential tosyl and ester cleavage, and a reduction of the olefin under hydrogenation conditions (Scheme 4).
  • Common intermediate 6 can be converted to compounds such as 13 via Suzuki coupling, to install the C5 moiety, followed by concomitant olefin reduction and benzyl cleavage, and saponification of the ethyl ester (Scheme 6).
  • common intermediate 8 can be used in this reaction sequence to generate compounds such as 14.
  • Scheme 7 Shown in Scheme 7 are various strategies to incorporate heterocycles at the C5 position of Formula I.
  • deprotonation of a given heterocycle such as thiazole
  • Subsequent transformations similar to the schemes above can be used to generate the thiazole derivative 15.
  • Cyclopentenone can also react with nitrogen nucleophiles to form 1,4-addition products with heterocycles such as pyrazole.
  • Subsequent transformations similar to the schemes above can be used to generate the pyrazole derivative 16.
  • 3-iodo-cyclopentenone may participate in a Suzuki coupling with heterocyclic boronate esters, such as the N-methylpyrazole boronate shown in Scheme 7. Again, subsequent transformations similar to the schemes above can be used to generate the N- methylpyrazole derivative 17.
  • Scheme 8 displays a route toward oxazole derivative 18.
  • the propargyl amide generated from 3-carboxy-cyclopentanone, can be cyclized with mercury salts to the cyclopentanone oxazole (J. Med. Chem. 1990, 33, 1128), followed by the subsequent transformations described in the schemes above to afford oxazole derivative 18.
  • Scheme 9 displays a route toward thiazole regio-isomer 21.
  • Stannylation of 3-ethoxy- cyclopentenone can generate intermediate 19, and conversion of 2,4-dibromo-thiazole to 20 allows for regio-control in the subsequent Stille coupling.
  • coupling of 19 and 20 provides the beta- substituted cyclopentenone intermediate, which following the subsequent transformations described in the schemes above, can afford thiazole derivative 21.
  • the various organic group transformations and protecting groups utilized herein can be performed by a number of procedures other than those described above. References for other synthetic procedures that can be utililized for the preparation of intermediates or compounds disclosed herein can be found in, for example, M.B. Smith, J.
  • racemic mixtures of compounds may be separated so that individual enantiomers are isolated.
  • This separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds of Formula I to an enantiomerically pure compound to form a diastereomeric mixture, which is then separated into individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction can be, but is not limited to, the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to substantially pure enantiomers by cleaving the added chiral residue from the diastereomeric compound.
  • racemic mixture of the compounds of Formula I can also be separated directly by chromatographic methods utilizing chiral stationary phases, the methods of which are well known in the art. Additional methods for the resolution of optical isomers can be used, and will be apparent to the average worker skilled in the art. Such methods include, but are not limited to, those discussed by J. Jaques, A. Collet, and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981). Alternatively, enantiomers of compounds of the general Formula I may be obtained by asymmetric stereoselective synthesis using optically pure starting materials or reagents, obtained either from the chiral pool or from synthetic sources. Such asymmetric synthetic methods include, but are not limited to, those discussed by J.D. Morrison, Ed. Asymmetric Synthesis; Academic Press: Orlando, Volume 5, (1985).
  • the compounds described herein may also exist as tautomers, which have different points of attachment for hydrogen accompanied by one or more double bond shifts.
  • a ketone and its enol form are keto-enol tautomers.
  • the proton of a pyrazole may reside on either of the two nitrogens within the heterocyclic ring.
  • Formula I and the formulae described herein are intended to represent all individual tautomers and mixtures thereof, unless stated otherwise.
  • DMF is dimethylformamide
  • DCM is dichloromethane (methylene chloride)
  • TFA is trifluoroacetic acid
  • TBAF is tetrabutylammonium fluoride
  • TFAA is trifluoroacetic anhydride
  • LDA is lithium diisopropyl amide
  • EDC(I) is l ⁇ ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; NHS is N-hydroxy succinimide; TsCl is toluenesulfonyl (tosyl) chloride; dppf is l,l'-bis(diphenylphosphino)ferrocene;
  • UV ultraviolet
  • (ee) is enantiomeric excess.
  • This material (25 mg, 0.079 mmol) was diluted into water (1 mL) and isopropanol (2 mL), and the turbid mixture treated with sodium azide (10 mg, 0.16 mmol) and ZnBr 2 (26 mg, 0.12 mmol).
  • the heterogeneous reaction mixture was refluxed for 16 h, cooled to room temperature, acidified to pH 2 with cone. HCl, extracted with EtOAc, and the organic phase dried over anhydrous sodium sulfate, and concentrated in vacuo.
  • the benzyl-protected olefinic intermediate (17 mg, 0.047 mmol) was then diluted into methanol (2 mL), and the turbid mixture brought to homogeneity with the dropwise addition of concentrated HCl.
  • Catalytic Pd-C (10% by weight) was added, and the reaction mixture stirred vigorously under 1 atmosphere of hydrogen gas (balloon) for 48 h. The reaction mixture was filtered and concentrated in vacuo to provide the desired product.
  • EXAMPLE 2 utilized a microwave reactor for facilitation of the palladium coupling reaction.
  • EXAMPLE 2 was conducted under thermal conditions (85 0 C, 2 h), with the use of potassium phosphate as base.
  • EXAMPLE 2 (500 MHz, CD 3 OD) ⁇ 2.95 (m, 2H), 3.40 (m, 2H), 4.27 (m, IH), 7.20-7.40 (m, 5H).
  • EXAMPLE 3 (500 MHz, CD 3 OD) ⁇ 2.95 (m, 2H), 3.40 (m, 2H), 4.45 (bd, IH), 7.05-7.40 (m, 4H).
  • EXAMPLE 4 (500 MHz, CD 3 OD) 6 2.29 (s, 3H), 2.95 (m, 2H), 3.30 (m, 2H), 4.25 (m, IH), 7.05 (m, IH), 7.20 (m, 3H).
  • EXAMPLE 5 (500 MHz, CD 3 OD) ⁇ 2.99 (m, 2H), 3.36 (m, 2H), 4.35 (m, IH), 7.55 (d, 2H), 7.65 (d, 2H).
  • EXAMPLE 8 (500 MHz, CD 3 OD) ⁇ 2.90 (bm, 2H), 3.40 (bm, 2H), 4.30 (bs, IH), 6.81 (bt, IH), 6.96 (bd, 2H).
  • EXAMPLE 9 (500 MHz, CD 3 OD) ⁇ 2.95 (m, 2H), 3.40 (m, 2H), 4.40 (m, IH), 7.00 (m, IH), 7.10 (m, 2H).
  • EXAMPLE 10 (500 MHz, CD 3 OD) ⁇ 3.05 (m, 2H), 3.20 (m, 2H), 4.64 (m, IH), 6.99 (t, 2H), 7.31 (m, IH).
  • EXAMPLE 16 (500 MHz, CD 3 OD) ⁇ 1.25 (d, 6H), 2.95 (m, 3H), 3.40 (m, 2H), 4.20 (m, IH), 7.18 (d, 2H), 7.26 (d, 2H).
  • EXAMPLE 17 (500 MHz, CD 3 OD) ⁇ 2.90 (m, 2H), 3.40 (m, 2H), 4.25 (m, IH), 7.40 (bq, 4H).
  • EXAMPLE 18 (500 MHz, CD 3 OD) ⁇ 2.40 (s, 3H) 2.90 (m, 2H), 3.30 (m, 2H), 4.51 (m, IH), 7.20 (m, 3H), 7.30 (d, IH).
  • EXAMPLE 19 (500 MHz, CD 3 OD) ⁇ 2.95 (m, 2H), 3.40 (m, 2H), 4.30 (bm, IH), 7.40 (m, 4H).
  • EXAMPLE 20 (500 MHz, CD 3 OD) ⁇ 2.95 (m, 2H), 3.40 (m, 2H), 4.30 (bm, IH), 7.40 (m, 4H).
  • the crude product was purified by preparative centrifugal chromatography (Si ⁇ 2 , 20%EtOAc- hexane) to afford the beta-substituted enone intermediate.
  • This material (1.5 g, 4.8 mmol) was diluted into ethanol (100 mL), treated with potassium tert-butoxide (IM t-BuOH, 5.3 mL, 5.3 mmol) and diethyl oxalate (778 mg, 5.3 mmol) after which the colorless reaction mixture turns red.
  • the reaction mixture was maintained for 1 h, monitored by LCMS, and then treated with hydrazine-hydrochloride (361 mg, 5.3 mmol).
  • reaction mixture was maintained for 15 h, concentrated in vacuo, diluted with (1 : 1) EtO Ac-water, the organic phase separated, dried over anhydrous sodium sulfate, and concentrated in vacuo.
  • the residue was purified by preparative centrifugal chromatography (SiO 2 , 50%EtOAc-hexane) to afford the olefinic pyrazole ethyl ester.
  • This olefin intermediate was reduced by treatment with ammonium formate (5 equivalents), formic acid (4 equivalents), and Pd-C (1 equivalent), in ethanol- water (7:1, 0.1 M).
  • the reaction mixture was heated in a re-sealable pressure tube at 85 0 C for 12 h, then cooled, filtered, concentrated in vacuo, partitioned between water and EtOAc, and the organic phase separated, dried over anhydrous sodium sulfate, and concentrated in vacuo.
  • the crude ester (63 mg, 0.203 mmol) was diluted into water-THF (1:1, 2 mL) and treated with LiOH (14.5 mg, 0.609 mmol).
  • the reaction mixture was maintained for 18 h, concentrated in vacuo to a small volume of water, acidified to pH 2, extracted with EtOAc, and the organic partition dried over anhydrous sodium sulfate and concentrated in vacuo.
  • the residue was purified by preparative reverse phase HPLC on a Gilson system to afford the desired product.
  • reaction mixture was maintained at room temperature for 2 h, quenched with saturated aqueous sodium bicarbonate, concentrated, partitioned between water and methylene chloride, and the organic partition dried over anhydrous sodium sulfate and concentrated in vacuo.
  • This nitrile intermediate (67 mg, 0.25 mmol) was combined with sodium azide (33 mg, 0.51 mmol) and ZnBr 2 (57 mg, 0.25 mmol), and diluted with (10: 1) isopropanol-water (1.1 mL).
  • the reaction mixture was heated at 85 0 C in a re-sealable pressure tube for 24 h, cooled, concentrated, filtered, and purified by preparative reverse phase HPLC on a Gilson system to afford the desired product.
  • EXAMPLE 40 (500 MHz, CD 3 OD) ⁇ 2.05 (m, 2H), 2.90 (m, 3H), 3.20 (d, 2H), 7.00 (dd, 2H).
  • EXAMPLES 47 and 49 were synthesized via lithium-halide exchange of 2-bromopyridine with n-butyllithium, and 2-chloropyrazine with lithium tetramethylpiperidinyl amide, respectively.
  • the 3-(pyrazinyl)-cyclopentenone intermediate of EXAMPLE 49 was carried through similar transformations shown in Scheme 7, including diethyl oxalate acylation, pyrazole formation, hydrogenation, and LiOH saponification of the final ethyl ester.
  • EXAMPLE 50 was synthesized via meta- broniopyridine exchange with isopropyl magnesium chloride to generate the 3-pyridyl Grignard reagent.
  • EXAMPLE 52 was prepared from 1,2,3-triazole under conditions similar to those described in EXAMPLE 51 above and illustrated in Scheme 7.
  • this material was treated with potassium tert-butoxide and diethyl oxalate in ethanol, followed by hydrazine-hydrochloride to afford the olefmic pyrazole ethyl ester.
  • This olefin ester intermediate was reduced by treatment with ammonium formate, formic acid, Pd-C, and saponified in a similar manner with aqueous NaOH. The residue was purified by preparative reverse phase HPLC on a Gilson system to afford the desired product.
  • 3-carboxy-cyclopentanone 100 mg, 0.78 mmol was diluted into benzene (20 mL), treated with thionyl chloride (0.093 mL, 0.78 mmol), and the reaction mixture heated at reflux for 2 h. The mixture was then concentrated, diluted with methylene chloride (20 mL), cooled to 0 0 C, and propargyl amine added (78 mg, 0.86 mmol), followed by triethylamine (0.33 mL, 2.3 mmol). The reaction mixture was aged for 12 h, then partitioned with saturated aqueous sodium bicarbonate, the organic partition dried over anhydrous sodium sulfate and concentrated in vacuo.
  • Step 2 4-(Methylthio)nicotinaldehyde To a solution of NaSMe (9.5 g, 135 mmol) in MeOH (250 mL) was added the 4- chloronicotinaldehyde (13.5 g, 94.4 mmol) of Step 1 in MeOH (250 mL). The reaction mixture was maintained at 60 0 C for 15 min. The reaction mixture was poured over NH4CI and EtOAc. The organic phase was separated, washed with H2O and dried over Na2SO4.
  • Step 4 Methyl 4-(methylthio)- 1 H-pyrrolo [2,3 -bipyridine-2-carboxylate
  • xylenes 16 mL
  • xylenes 16 mL
  • the yellow solution was cooled to room temperature. Precaution must be taken due to the possibility of an exotherme due to the formation of nitrogen.
  • the suspension was then cooled to 0 0 C, filtered and washed with xylene to provide the title compound.
  • Step 5 Ethyl 4-(methylthio)-6-oxo-6J,8.9-tetrahvdropyrido[3,2-b]indolizine-7-carboxylate To a solution of the compound of Step 4 (0.35 g, 1.6 mmol) in DMF (20 mL) at 0 0 C was added NaH (1.2 eq.). After a period of 5 min., nBu4NI (0.10 g) and ethyl 4-bromobutyrate (0.40 mL). were added. After a period of 1 h at room temperature, the reaction mixture was poured over saturated NH4CI and EtOAc.
  • Step 8 Ethyl r4-(methylthio)-6,7,8,9-tetrahvdropyrido
  • Step 7 The compound of Step 7 was dissolved in MeOH - THF using heat for dissolution. To the previous cooled solution was added at room temperature Pt ⁇ 2 and the resulting mixture was maintained for 18 h under an atmospheric pressure of hydrogen. The reaction mixture was filtered carefully over Celite using CH2CI2. The filtrate was evaporated under reduced pressure to provide the title compound.
  • the compound of Step 7 can be hydrogenated with Pd (OH)2 in EtOAc at
  • Step 9 Ethyl r4-(methylsulfonyl)-6,7,8,9-tetrahydropyridor3,2-blindolizin-6-yl1acetate
  • Step 8 To the compound of Step 8 (0.08 g, 0.27 mmol) in MeOH (3.0 mL) were added Na2WO4 (0.10 g) and 30% H2O2 (600 ⁇ L). After a period of 1 h, the reaction mixture was partitioned between H2O and EtOAc. The organic phase was washed with H2O, separated and evaporated. The title compound was purified by flash chromatography.
  • Step 10 Ethyl r5-r(4-chlorophenyl)thiol-4-rmethylsulfonylV6.7.8,9-tetrahvdropyrido[3.2- biindolizin-o-yliacetate
  • SO2CI2 50 ⁇ L
  • DMF 2.0 mL
  • the previous mixture ( « 180 ⁇ L).
  • the reaction was followed by lH NMR and maintained at room temperature until no starting material remained.
  • the reaction mixture was poured over saturated NaHCO3 and EtOAc.
  • the organic phase was separated, evaporated and the title compound purified by flash chromatography. 6-yl] acetic acid
  • the title compound can be prepared from the compound of Example 1, Step 8 in a similar manner as described in Example 1, Step 10 and 11. m/z 418.
  • Step 1 Ethyl r5-(4-chlorobenzoyl)-4-(methylthioV6,7,8,9-tetrahvdropyridor3,2-b1mdolizin-6- yl] acetate
  • Example 1 Step 2 As described in Example 1 Step 2 except the solution was heated at 55°C for 2 hr.
  • Step 2 MethvU2Z-2-azido-3-[2-(methylthio)pyridin-3-yllprop-2-enoate
  • the title compound was prepared as described in Example 1 Step 3.
  • Step 5 l-(Methylthio)-6.7-dihvdro-8H-pyridof3,4-b1pyrrolizin-8-one Methyl 1 -(methylthio)-8-oxo-7,8-dihydro-6H-pyrido[3,4-b] pyrrolizine-7-carboxylate was converted to the title compound as described in Example 1 Step 6. Step 6 Methyl r ⁇ -hvdroxy-l-fmethylthioVy ⁇ -dihvdro- ⁇ -pyridorS ⁇ -blpyrrolizin- ⁇ -yljacetate
  • Step 8 Methyl ri-(methylsulfonyl)-7.8-dihvdro-6H-pyrido[3,4-b1pyrrolizin-8-yllacetate
  • Step 3 Methyl [l-( " methylthio)-7,8-dihvdro-6H-pyridor3,4-blpyrrolizm-8-yl1-acetate
  • Step 1 Ethyl ri-(methylsulfonyl)-6,7,8,9-tetrahydropyrido[3,4-b1indolizin-9-yllacetate
  • Step 2 riO-rCS ⁇ -DichlorophenvDsulfanvn-l-rmethylsulfonylVej.S.g-tetrahvdropyridorS ⁇ - blindolizin-9-yllacetic acid
  • Step 1 was converted to the title compound in the same manner as
  • the title compound was prepared as described in Example 1 using bis(2,4- dichlorophenyl)disulfide.
  • the disulfide was prepared from 2,4-dichlorothiophenyl using Br2 in ether.
  • lH NMR 500 MHz, acetone-d ⁇ ) ⁇ 8.55 (d,lH), 7.85 (d, IH), 7.35 (s, IH), 7.00 (d, IH), 6.65 (d, IH), 4.55 (m, IH), 4.15 (m, IH), 3.80 (m, IH), 3.35 (s, 3H), 2.80 to 2.10 (m, 6H).
  • Step 1 (+/-)-(7-Fluoro-l,2,3,4-tetrahvdrocvclopentarb1indol-3-yl)acetic acid ethyl ester.
  • reaction mixture was quenched by the addition of IN HCl and this mixture was poured into a separatory funnel containing brine/EtOAc. The layers were separated and the organic layer was washed with water, brine, dried over anhydrous Na2SC"4 and concentrated. This material was used without further purification in the next step.
  • Step 4 (+/-)-r5-bromo-4-(4-chlorobenzyl)-7-fluoro-l,2,3,4-tetrahvdrocvclopentarblindol-3-yl1- acetic acid
  • reaction was quenched by the addition of 2 mL of AcOH and this mixture was poured into a separatory funnel containing IN HCl/EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The alkylated material was hydrolyzed using the procedure described in Step 2. The crude material was further purified by trituration with EtOAc/hexanes to provide the title compound.
  • Step 5 r+V[5-bromo-4-(4-chlorobenzyl)-7-fluoro-l,2,3,4-tetrahvdrocyclopenta[b1indol-3- yl) acetic acid
  • Step 6 (-)-[4-(4-chlorobenzyl)-7-fluoro-5-(methanesulfonyl)-l,2,3,4-tetrahvdrocvclopenta[b]- indol-3-vU acetic acid and sodium salt
  • the acid from Step 5 (15.4 g) was first esterified with diazomethane.
  • the sulfonylation was accomplished by mixing the ester thus formed with 16.3 g of methanesulfinic acid sodium salt and 30.2 g of CuI (I) in N-methylpyrrolidinone.
  • the suspension was degassed under a flow of N2, heated to
  • Step 1 (+/-)-7-fluoro-l,2,3,4-tetrahvdrocvclopentarb1indol-3-yl)acetic acid dicyclohexylamine
  • the reaction mixture was heated to 115 0 C for 5 hours and allowed to cool to room temperature.
  • 3N KOH (3 eq) was then added and the mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was diluted with water (1.0 volume), washed with toluene (3x0.75 volume).
  • the aqueous phase was acidified to pH 1 with 3N HCl and extracted with tertbutyl methyl ether (2x0.75 volume).
  • Step 2 ( r +/-)-( ' 5-bromo-7-£luoro-l,2,3,4-tetrahvdrocvclopenta[ ' b]indol-3-vDacetic acid
  • DCHA salt from Step 1 above in dichloromethane (0.241 M solution) was cooled to -20 to -15 0 C.
  • Pyridine (2 eq.) was added in one shot and to the slurry was added dropwise bromine (2.5 eq.) over 30 to 45 minutes maintaining the temperature between -20 0 C and -15 0 C. (At about 1/3 addition of bromine, the reaction mixture was thick and an efficient stirring was needed.
  • the reaction mixture was switched to methyl t-butyl ether (MTBE, 0.8 volume) and a 10% aqueous acetic acid solution (0.8 volume) was added.
  • MTBE methyl t-butyl ether
  • the mixture (crystallization of salts, e.g pyridium) was aged at room temperature for 1 hour and filtered through solka-floc.
  • the pad of solka-floc was rinsed with MTBE (ca. 0.2 volume) and the filtrate (biphasic, MTBE/aqueous) was transferred into an extractor.
  • the organic phase was washed with water (0.8 volume).
  • the MTBE extract was concentrated and switched to isopropyl alcohol (IPA, 0.25 volume) to crystallize the compound. Water (0.25 volumes) was added and the batch was aged for 1 hour.
  • IPA isopropyl alcohol
  • the bromoacid of Step 2 was dissolved in dimethylacetamide (0.416 M solution) and cesium carbonate (2.5 eq.) was added in one portion.
  • cesium carbonate 2.5 eq.
  • 4- chlorobenzyl chloride 2.5 eq.
  • the batch was heated to 50 0 C for 20 h.
  • the batch was cooled to r.t. and sodium hydroxide 5N (4.00 eq.) was added over 5 minutes (temperature rose to +40 0 C).
  • the reaction was aged at 50 0 C for ca. 3 hours, cooled to room temperature and transferred into an L extractor.
  • the solution was diluted with isopropylacetate (IPAc, 2 volumes) and cooled to +15 0 C.
  • IPAc isopropylacetate
  • the final reaction mixture was warmed to -78°C and stirred at that temperature for 1.5h.
  • the reaction mixture was poured into cold aqueous HCl (3N, 800 mL) and stirred for 5 min.
  • Aqueous concentrated NH 4 OH was added to adjust pH to 7.5.
  • the aqueous layer was extracted three times with EtOAc.
  • the combined organic layer was washed with aqueous NH 4 Cl and brine, dried over anhydrous N a 2SO 4 , filtered and concentrated.
  • the crude material was further purified by a pad of silica gel by eluting with a gradient from 100% hexanes to 100% EtOAc and the product was crystallized in cold hexanes to yield the title compound as a pale yellow solid.
  • Step 5 l-Chloro-6J-dihvdro-8H-pyridor3,4-61pyrrolizin-8-one
  • isopropanol 8.0 mL
  • concentrated HCl 2.0 mL
  • the reaction mixture was partitioned between EtOAc and Na2CO3. The organic phase was separated, evaporated to provide the title compound.
  • Step 6 l-Isopropenyl-6,7-dihvdro-8 ⁇ -pyrido[3,4-b]pyrrolizin-8-one
  • l-chloro-6,7-dihydro-8H-pyrido[3,4-b]pyrrolizin-8-one 5.0 g, 24.3 mmol
  • tris (dibenzylidene acetone)dipalladium (0) 1.0 g, 1.09 mmol
  • triphenylarsine 2.70 g, 8.82 mmol
  • tributylisopropenyl stannane 9.60 g, 29.00 mmol.
  • Step 8 Ethyl (l-isopro ⁇ yl-7,8-dihvdro-6H-pyrido[3 n 4-blpyrrolizin-8-yl)acetate
  • Step 9 Ethyl (9-r(3.4-dichlorophenvnthio1-l-isopropyl-7.8-dihvdro-6H-pyrido T3.4- b1pyrrolizin-8-yl) acetate
  • Step 10 ig-rO ⁇ -DichlorophenvDthioi-l-isopropyl-y.S-dihvdro- ⁇ H-pyridofS ⁇ -blpyrrolizin-S- yl I acetic acid
  • Step 10 The product of Step 10 was converted to its methyl ester using CH 2 N 2 , and the ester was subjected to HPLC separation on chiral stationary phase (chiralcel OD column 2x25cm), eluting with 12% 2-propanol in hexane at a flow rate of 6 mL/min.
  • Enantiomer A (less polar) has a retention time of 31.9 min and Enantiomer B (more polar) has a retention time of 35.5 min. Both A and B were hydrolyzed as in Ex. 17 Step 10 to give enantiomers A and B of the title compound.
  • Step 3 (+/-) -Ethyl r ⁇ -fluoro-S-fmethylsulfonvD ⁇ .g-tetrahvdro-lH-carbazol-l-vn-acetate
  • sodium methanesulphinate (3 eq) and copper iodide (3 eq) were added to a solution of the compound of Step 2 (1 eq) in anhydrous DMSO (0.28M) were added sodium methanesulphinate (3 eq) and copper iodide (3 eq). N 2 was bubbled into the mixture for 5 min and the reaction was then stirred at 100 0 C under N 2 atmosphere.
  • step 3 The racemic mixture from step 3 was resolved by preparative ⁇ PLC on a chiralpak AD preparative column eluted with a mixture of 15% iPrO ⁇ in hexane. The more polar enantiomer (longer retention time) was identified as the title compound based on the activity of the final product.
  • Step 5 Ethyl rriRV9-rriS)-l-C4-chlorouhenvnethvn-6-fluoro-8-rmethylsulfonylV2.3.4.9- tetrahydro- lH-carbazol- 1 -yli acetate
  • Step 6 rdRVg-r ⁇ SVl- ⁇ -ChlorophenvDethyli- ⁇ -fluoro- ⁇ -CmethylsulfonyD ⁇ J ⁇ -tetrahvdro- lH-carbazol- 1 -yl] acetic acid and [( 1 S V 9-1Y 1 S)- 1 -(4-chlorophenyl)ethyl1 -6-fluoro-8-(methylsulfonyl)- 2,3 A9-tetrahydro- 1 ⁇ -carbazol- 1 -yl] acetic acid
  • 1 mixture of T ⁇ F and methanol 0.
  • Step 7 Methyl rdRV ⁇ -fluoro- ⁇ -CmethylsulfonvD ⁇ .S ⁇ -tetrahvdro-lH-carbazol-l-yllacetate
  • Step 8 (fl ⁇ V6-Fluoro-8-fmethylsulfonylV9-(fl. ⁇ -l-r4-(1rifluorome1hv ⁇ phenyl1ethyll-2,3,4.9- tetrahydro-lH-carbazol-1-vDacetic acid (Compound AJ)
  • CHO-KI cells stably expressing the niacin receptor were used to make membrane for binding analysis.
  • Cells were grown to ⁇ 80% confluence in growth medium (F-12 Kaighn's modified medium (ATCC, #30-2004) containinglO%FBS (GIBCO, #10438-026), lmg/ml G418 (GIBCO, #10131- 027) and IX Pen-Strep (Sigma P-0871), harvested by scraping, and centrifuged at 12 000 X g, 4° Celsius, 10 minutes.
  • growth medium F-12 Kaighn's modified medium (ATCC, #30-2004) containinglO%FBS (GIBCO, #10438-026), lmg/ml G418 (GIBCO, #10131- 027) and IX Pen-Strep (Sigma P-0871), harvested by scraping, and centrifuged at 12 000 X g, 4° Celsius, 10 minutes.
  • Cell pellets were resuspended in harvest buffer (20 mM HEPES, 10 mM EDTA, pH 7.4) and homogenized with 4 X 10 second bursts of a 12 mm Polytron homogenizer, setting 5. Lysate was centrifuged at 2 000 X g, 4°, 10 minutes to remove unlysed cells and nuclei, and the resulting supernatant centrifiiged at 39 000 X g, 4°, 45 minutes to pellet membranes.
  • the resulting pellet was resuspended in wash buffer (20 mM HEPES, 0.1 mM EDTA, pH 7.4), homogenized with 3 X 10 second bursts of a 12 mm Polytron, setting 4, and re-centrifuged at 39 000 X g, 4°, 45 minutes.
  • the resulting pellet was resuspended in wash buffer and stored in liquid nitrogen before use.
  • the concentration of membrane proteins in this preparation was determined using the Pierce BCA protein assay, with BSA as a standard. Equilibrium binding of 3 H-nicotinic acid was performed in 96-well polypropylene plates.
  • Reactions contained 140 ⁇ l membrane diluted in assay buffer (20 mM HEPES, pH 7.4, 1 mM MgC12, and 0.01% CHAPS; 15-30 ⁇ g membrane protein/assay), 20 ⁇ l test compounds diluted in assay buffer (compound stocks were in 100% DMSO; final DMSO concentration in the assay was 0.25%), and 40 ⁇ l 250 nM tritiated niacin ([5, 6- 3 H] - nicotinic acid: American Radiolabeled Chemicals, Inc. ,20 ⁇ M in ethanol; final ethanol concentration in each assay was 1.5%).
  • Non-specific binding was determined in the presence of 250 ⁇ M unlabeled nicotinic acid.
  • test compounds are initially assayed at 1 and 0.1 ⁇ M and then at a range of concentrations chosen such that the middle dose would cause about 50% inhibition of a Radioligand binding (i.e., IC 50 ).
  • IC 50 is determined from an inhibition response curve, logit-log plot of % B/B o vs concentration of test compound.
  • Kj is calculated by the Cheng and Prustoff transformation: where [L] is the concentration of a Radio-Ligand used in the assay and K D is the dissociation constant of a Radio-Ligand determined independently under the same binding conditions.
  • Certain compounds of formula I have an IC 50 in this niacin binding assay within the range of about 0.010-50 ⁇ M. More advantageous compounds of the invention have an IC 50 value in this assay within the range of about 0.01-10 ⁇ M. Still more advantageous compounds have an IC 50 value in this assay within the range of about 0.010-1.0 ⁇ M.
  • Membranes prepared from Chinese Hamster Ovary (CHO)-Kl cells stably expressing the niacin receptor or vector control (7 ⁇ g/assay) were diluted in assay buffer (100 mM HEPES, 100 mM NaCl and 10 mM MgCl 2, pH 7.4) in Wallac Scintistrip plates and pre-incubated with test compounds diluted in assay buffer containing 40 ⁇ M GDP (final [GDP] was 10 ⁇ M) for ⁇ 10 minutes before addition Of 35 S-GTPyS to 0.3 nM. To avoid potential compound precipitation, all compounds were first prepared in 100% DMSO and then diluted with assay buffer resulting in a final concentration of 3% DMSO in the assay.
  • assay buffer 100 mM HEPES, 100 mM NaCl and 10 mM MgCl 2, pH 7.4
  • Binding was allowed to proceed for one hour before centrifuging the plates at 4000 rpm for 15 minutes at room temperature and subsequent counting in a TopCount scintillation counter. Non-linear regression analysis of the binding curves was performed in GraphPad Prism.
  • CHO-Kl cell culture medium F-12 Kaighn's Modified Cell Culture Medium with 10% FBS, 2 mM L- Glutamine, 1 mM Sodium Pyruvate and 400 ⁇ gml G418
  • Guanosine 5 '-diphosphate sodium salt (GDP, Sigma-Aldrich Catalog #87127)
  • Binding Buffer 20 mM HEPES, pH 7.4 10O mM NaCl 1O mM MgCl 2 GDP Buffer: binding buffer plus GDP, ranging from 0.4 to 40 ⁇ M, make fresh before assay
  • Certain compounds of formula I have an EC 50 in this functional GTPyS binding assay within the range of about 0.010-100 ⁇ M. More advantageous compounds of the invention have an EC 50 value in this assay within the range of about 0.010-10 ⁇ M. Still more advantageous compounds have an EC 50 value in this assay of less than about 1 ⁇ M, about 0.01-1 ⁇ M.
  • mice Male C57B16 mice ( ⁇ 25g) are anesthetized using 10mg/ml/kg Nembutal sodium. When antagonists are to be administered they are co-injected with the Nembutal anesthesia. After ten minutes the animal is placed under the laser and the ear is folded back to expose the ventral side. The laser is positioned in the center of the ear and focused to an intensity of 8.4-9.0 V (with is generally ⁇ 4.5cm above the ear). Data acquisition is initiated with a 15 by 15 image format, auto interval, 60 images and a 20 sec time delay with a medium resolution. Test compounds are administered following the 10th image via injection into the peritoneal space. Images 1-10 are considered the animal's baseline and data is normalized to an average of the baseline mean intensities. .
  • Non-esterified free-fatty acid (NEFA) assays are done on serum derived from live, freely moving rats. Catheters are surgically implanted into femoral veins and the animals are used within one week of arrival. Food is removed from the animals approximately 16 hours prior to the assay. A draw of ⁇ 200 ⁇ l blood is pulled from the catheter and represents the baseline NEFA serum sample. Drug is administered intra-peritoneally (IP) or orally (po) at various concentrations to individual rats and then ⁇ 200 ⁇ l blood draws are pulled from the catheter at the indicated time points for further NEFA analysis.
  • IP intra-peritoneally
  • po orally
  • NEFA assays are performed according to the manufacturer's specifications (Wako Chemicals, USA; NEFA C) and free fatty acid concentrations are determined via regression analysis of a known standard curve (range of known free fatty acids). Data is analyzed using Excel and PrismGraph.

Abstract

L'invention porte sur des composés de formule (I), et leurs sels et hydrates pharmacocompatibles qui s'avèrent utiles pour traiter les dyslipidémies, et sur des préparations pharmaceutiques et leurs méthodes d'utilisation.
PCT/US2006/012876 2005-04-13 2006-04-07 Agonistes du recepteur de la niacine, compositions les contenant et methodes de traitement WO2006113150A1 (fr)

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AU2006236939A AU2006236939A1 (en) 2005-04-13 2006-04-07 Niacin receptor agonists, compositions containing such compounds and methods of treatment
EP06740649A EP1874301A4 (fr) 2005-04-13 2006-04-07 Agonistes du recepteur de la niacine, compositions les contenant et methodes de traitement
JP2008506525A JP2008536846A (ja) 2005-04-13 2006-04-07 ナイアシン受容体アゴニスト、かかる化合物を含有する組成物及び治療方法
CA002603757A CA2603757A1 (fr) 2005-04-13 2006-04-07 Agonistes du recepteur de la niacine, compositions les contenant et methodes de traitement
US11/918,270 US20090054423A1 (en) 2005-04-13 2006-04-07 Niacin receptor agonists, compositions containing such compounds and methods of treatment

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WO2008017381A1 (fr) 2006-08-08 2008-02-14 Sanofi-Aventis Imidazolidin-2,4-dione arylaminoaryl-alkyl-substituée, son procédé de fabrication, médicament contenant ce composé et son utilisation
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
DE102007063671A1 (de) 2007-11-13 2009-06-25 Sanofi-Aventis Deutschland Gmbh Neue kristalline Diphenylazetidinonhydrate, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2010003624A2 (fr) 2008-07-09 2010-01-14 Sanofi-Aventis Composés hétérocycliques, leurs procédés de préparation, médicaments comprenant lesdits composés et leur utilisation
WO2010068601A1 (fr) 2008-12-08 2010-06-17 Sanofi-Aventis Hydrate de fluoroglycoside hétéroaromatique cristallin, ses procédés de fabrication, ses procédés d'utilisation et compositions pharmaceutiques le contenant
WO2011023754A1 (fr) 2009-08-26 2011-03-03 Sanofi-Aventis Nouveaux hydrates de fluoroglycoside hétéroaromatiques cristallins, substances pharmaceutiques comprenant ces composés et leur utilisation
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US9238077B2 (en) 2009-09-01 2016-01-19 Catabasis Pharmaceuticals, Inc. Fatty acid niacin conjugates and their uses
USRE46608E1 (en) 2009-09-01 2017-11-14 Catabasis Pharmaceuticals, Inc. Fatty acid niacin conjugates and their uses

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3978044A (en) * 1974-05-02 1976-08-31 Science Union Et Cie Indazole derivatives, processes for making the same and pharmaceutical compositions

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6410583B1 (en) * 2000-07-25 2002-06-25 Merck Frosst Canada & Co. Cyclopentanoindoles, compositions containing such compounds and methods of treatment
JP2005518362A (ja) * 2001-11-21 2005-06-23 メルク　エンド　カムパニー　インコーポレーテッド 脂質異常状態を治療するための治療用化合物
US6902902B2 (en) * 2001-11-27 2005-06-07 Arena Pharmaceuticals, Inc. Human G protein-coupled receptors and modulators thereof for the treatment of metabolic-related disorders
AR038136A1 (es) * 2002-01-24 2004-12-29 Merck Frosst Canada Inc Cicloalcanindoles con sustitucion con fluor composiciones que contienen estos compuestos y metodos de tratamiento
GB0319124D0 (en) * 2003-08-14 2003-09-17 Smithkline Beecham Corp Chemical compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3978044A (en) * 1974-05-02 1976-08-31 Science Union Et Cie Indazole derivatives, processes for making the same and pharmaceutical compositions

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WO2008017381A1 (fr) 2006-08-08 2008-02-14 Sanofi-Aventis Imidazolidin-2,4-dione arylaminoaryl-alkyl-substituée, son procédé de fabrication, médicament contenant ce composé et son utilisation
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
DE102007063671A1 (de) 2007-11-13 2009-06-25 Sanofi-Aventis Deutschland Gmbh Neue kristalline Diphenylazetidinonhydrate, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2010003624A2 (fr) 2008-07-09 2010-01-14 Sanofi-Aventis Composés hétérocycliques, leurs procédés de préparation, médicaments comprenant lesdits composés et leur utilisation
WO2010068601A1 (fr) 2008-12-08 2010-06-17 Sanofi-Aventis Hydrate de fluoroglycoside hétéroaromatique cristallin, ses procédés de fabrication, ses procédés d'utilisation et compositions pharmaceutiques le contenant
WO2011023754A1 (fr) 2009-08-26 2011-03-03 Sanofi-Aventis Nouveaux hydrates de fluoroglycoside hétéroaromatiques cristallins, substances pharmaceutiques comprenant ces composés et leur utilisation
US9238077B2 (en) 2009-09-01 2016-01-19 Catabasis Pharmaceuticals, Inc. Fatty acid niacin conjugates and their uses
USRE46608E1 (en) 2009-09-01 2017-11-14 Catabasis Pharmaceuticals, Inc. Fatty acid niacin conjugates and their uses
USRE46605E1 (en) 2009-09-01 2017-11-14 Catabasis Pharmaceuticals, Inc. Fatty acid niacin conjugates and their uses
US9486534B2 (en) 2009-09-01 2016-11-08 Catabasis Pharmaceuticals, Inc. Niacin conjugated fatty acid mixtures and their uses
US9278136B2 (en) 2009-09-01 2016-03-08 Catabasis Pharmaceuticals, Inc. Fatty acid niacin conjugates and their uses
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
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